In all metazoans programmed cell death or apoptosis, is essential for proper development and maintenance of body homeostasis1. Apoptosis is triggered by caspases, members of a cysteine protease family that, when activated, lead to the distinct cellular changes observed in many, if not all, dying cells2. The decision to trigger apoptosis depends on the balance between factors that activate caspases and those that inhibit them. Inhibitor of Apoptosis Proteins (IAPs) are negative regulators of apoptosis, which bind to caspases and inhibit their activity3. Consistent with this role, inhibition of IAPs has been found to be an important step leading to caspase activation in mammals and Drosophila3.
Various disease states occur due to aberrant regulation of programmed cell death in an organism. For example, defects that result in a decreased level of apoptosis in a tissue as compared to the normal level required to maintain the steady-state of the tissue can result in an increased number of cells in the tissue. Such a mechanism of increasing cell numbers has been identified in various cancers, where the formation of a tumor occurs not because the cancer cells necessarily are dividing more rapidly than their normal counterparts, but because the cells are not dying at their normal rate. The first gene identified as being involved in a cell death pathway, the bc1-2 gene, was identified in cancer cells and was shown to function by decreasing the likelihood that cells expressing the gene would undergo apoptosis.
In comparison to cancer, where the likelihood of a cell undergoing apoptosis is decreased, various pathologies are associated with tissues containing cells undergoing a higher than normal amount of apoptosis. For example, increased levels of apoptosis are observed in various neuropathologies, including Parkinson's disease, Multiple Sclerosis, Alzheimer's disease, Huntington's disease and the encephalopathy associated with acquired immunodeficiency disease (AIDS). Since nerve cells generally do not divide in adults and, therefore, new cells are not available to replace the dying cells, the nerve cell death occurring in such diseases results in the progressively deteriorating condition of patients suffering from the disease.
The important role of IAPs in the regulation of apoptosis is evident from genetic studies in Drosophila. The Drosophila IAP1 (diap1) is encoded by the thread (th) locus. In loss of function diap1 mutants, apoptosis occurs in virtually all cells during early stages of embryogenesis4. The anti-apoptotic function of diap1 is blocked by IAP inhibitor (IAPi) proteins such as REAPER (RPR), HEAD INVOLUTION DEFECTIVE (HID) and GRIM5-7, forming an RHG family of proteins. IAP inhibition by RHG proteins is similarly crucial during apoptosis in mammals; the mitochondrially localized mammalian RHG proteins Smac/DIABLO and HtrA2 are released into the cytoplasm following apoptotic stimuli and relieve caspase inhibition by IAPs10-15.